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The Development of Carbohydrate-Based Influenza Virus Sialidase Inhibitors

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Influenza Virus Sialidase - A Drug Discovery Target

Part of the book series: Milestones in Drug Therapy ((MDT))

Abstract

This chapter presents a review of the development of influenza virus sialidase inhibitors based on a carbohydrate scaffold, predominantly that of the natural ‘ligand’ of the enzyme, N-acetylneuraminic acid (Neu5Ac). These inhibitors include hydrolytically stable substrate-like compounds, product mimics, and transition-state-like compounds. The major focus of the chapter, reflecting the most intensively researched area of inhibitor development, is on the use of the dihydropyran scaffold of the 2,3-unsaturated-Neu5Ac derivative, Neu5Ac2en, a putative transition state mimic. Structure-based drug design targeting conserved residues of the sialidase active site using this template leading to the development of the potent and selective inhibitor, and anti-influenza drug, zanamivir (Relenza™), as well as subsequent developments towards next generation inhibitors, are discussed.

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Abbreviations

NA:

Neuraminidase (sialidase)

Neu5Ac:

N-acetylneuraminic acid

Neu5Ac2en:

2-deoxy-2,3-didehydro-N-acetylneuraminic acid

MDCK:

Madin-Darby canine kidney (cell line)

References

  1. Colman PM, Varghese JN, Laver WG (1983) Structure of the catalytic and antigenic sites in influenza virus neuraminidase. Nature 303:41–44

    Article  PubMed  CAS  Google Scholar 

  2. Dyason JC, von Itzstein M (2011) Influenza virus sialidase and structure-based drug design. In: von Itzstein M (ed) Influenza virus sialidase: a drug discovery target. Springer, Heidelberg

    Google Scholar 

  3. Chan J, Bennet AJ (2011) Enzymology of influenza virus sialidase. In: von Itzstein M (ed) Influenza virus sialidase: a drug discovery target. Springer, Heidelberg

    Google Scholar 

  4. Rich JR, Gehle D, von Itzstein M (2007) Design and synthesis of sialidase inhibitors for influenza virus infections. In: Kamerling JP, Boons G-J, Lee Y, Suzuki A, Tanigichi N, Voragen AGJ (eds) Comprehensive glycoscience. Elsevier, Oxford, pp 885–922

    Chapter  Google Scholar 

  5. Chand P (2005) Recent advances in the discovery and synthesis of neuraminidase inhibitors. Expert Opin Ther Patents 15:1009–1025

    Article  CAS  Google Scholar 

  6. Flashner M, Kessler J, Tanenbaum SW (1983) The interaction of substrate-related ketals with bacterial and viral neuraminidases. Arch Biochem Biophys 221:188–196

    Article  PubMed  CAS  Google Scholar 

  7. Brossmer R, Holmquist L (1971) Specificity of neuraminidase. Synthesis of 5-N-acetyl-D-nonulosamine (5-acetamido-3,5-dideoxy-D-glycero-beta-D-galacto-nonulose) and 5-N-acetyl-D-neuraminamide (5-acetamido-3,5-dideoxy-D-glycero-β-D-galacto-nonulosonamide) and their methyl beta- and benzyl alpha-ketosides. Hoppe-Seyler’s Z Physiol Chem 352:1715–1719

    Article  PubMed  CAS  Google Scholar 

  8. Meindl P, Tuppy H (1966) Darstellung und enzymatische Spaltbarkeit von a-Ketosiden der N-Propionyl-, N-Butyryl- und N-Benzoyl-D-neuraminsäure. Monatsh Chem 97:1628–1647

    Article  CAS  Google Scholar 

  9. Brossmer R, Nebelin E (1969) Synthesis of N-formyl- and N-succinyl-D-neuraminic acid. On the specificity of neuraminidase. FEBS Lett 4:335–336

    Article  PubMed  CAS  Google Scholar 

  10. Meindl P, Bodo G, Palese P, Schulman J, Tuppy H (1974) Inhibition of neuraminidase activity by derivatives of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid. Virology 58:457–463

    Article  PubMed  CAS  Google Scholar 

  11. Varghese JN, McKimm-Breschkin JL, Caldwell JB, Kortt AA, Colman PM (1992) The structure of the complex between influenza virus neuraminidase and sialic acid, the viral receptor. Proteins 14:327–332

    Article  PubMed  CAS  Google Scholar 

  12. Hartshorn MJ (2002) AstexViewer: a visualisation aid for structure-based drug design. J Comput Aided Mol Des 16:871–881

    Article  PubMed  CAS  Google Scholar 

  13. Stoll V, Stewart KD, Maring CJ, Muchmore S, Giranda V, Gu Y-GY, Wang G, Chen Y, Sun M, Zhao C et al (2003) Influenza neuraminidase inhibitors: structure-based design of a novel inhibitor series. Biochemistry 42:718–727

    Article  PubMed  CAS  Google Scholar 

  14. Russell RJ, Haire LF, Stevens DJ, Collins PJ, Lin YP, Blackburn GM, Hay AJ, Gamblin SJ, Skehel JJ (2006) The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design. Nature 443:45–49

    Article  PubMed  CAS  Google Scholar 

  15. Burmeister WP, Henrissat B, Bosso C, Cusack S, Ruigrok RW (1993) Influenza B virus neuraminidase can synthesize its own inhibitor. Structure 1:19–26

    Article  PubMed  CAS  Google Scholar 

  16. Guo C-T, Sun X-L, Kanie O, Shortridge KF, Suzuki T, Miyamoto D, Hidari KIPJ, Wong C-H, Suzuki Y (2002) An O-glycoside of sialic acid derivative that inhibits both hemagglutinin and sialidase activities of influenza viruses. Glycobiology 12:183–190

    Article  PubMed  CAS  Google Scholar 

  17. Khorlin AY, Privalova IM, Zakstelskaya LY, Molibog EV, Evstigneeva NA (1970) Synthetic inhibitors of Vibrio cholerae neuraminidase and neuraminidases of some influenza virus strains. FEBS Lett 8:17–19

    Article  PubMed  CAS  Google Scholar 

  18. Suzuki Y, Sato K, Kiso M, Hasegawa A (1990) New ganglioside analogs that inhibit influenza virus sialidase. Glycoconjugate J 7:349–356

    Article  CAS  Google Scholar 

  19. Sabesan S, Neira S, Davidson F, Duus JØ, Bock K (1994) Synthesis and enzymatic, and NMR studies of novel sialoside probes: unprecedented, selective neuraminidase hydrolysis of and inhibition by C-6-(Methyl)-Gal sialosides. J Am Chem Soc 116:1616–1634

    Article  CAS  Google Scholar 

  20. Watts AG, Oppezzo P, Withers SG, Alzari PM, Buschiazzo A (2006) Structural and kinetic analysis of two covalent sialosyl-enzyme intermediates on Trypanosoma rangeli sialidase. J Biol Chem 281:4149–4155

    Article  PubMed  CAS  Google Scholar 

  21. von Itzstein M, Dyason JC, Oliver SW, White HF, Wu W-Y, Kok GB, Pegg MS (1996) A study of the active site of influenza virus sialidase: an approach to the rational design of novel anti-influenza drugs. J Med Chem 39:388–391

    Article  Google Scholar 

  22. von Itzstein M, Wu WY, Kok GB, Pegg MS, Dyason JC, Jin B, Van Phan T, Smythe ML, White HF, Oliver SW et al (1993) Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature 363:418–423

    Article  Google Scholar 

  23. Sabesan S, Neira S, Wasserman Z (1995) Structural and functional group tuning in the design of neuraminidase inhibitors. Carbohydr Res 267:239–261

    Article  PubMed  CAS  Google Scholar 

  24. Walop JN, Boschman TAC, Jacobs J (1960) Affinity of N-acetylneuraminic acid for influenza virus neuraminidase. Biochim Biophys Acta 44:185–186

    Article  PubMed  CAS  Google Scholar 

  25. Friebolin H, Supp M, Brossmer R, Keilich G, Ziegler D (1980) 1H-NMR investigations on the mutarotation of N-acetyl-O-neuraminic acid. Angew Chem Int Ed Engl 19:208–209

    Article  Google Scholar 

  26. Colman PM, von Itzstein LM, Varghese JN, Wu W-Y, Van Phan T, White HF [Biota Scientific Management Pty. Ltd., Australia] (1992) Anti-viral compounds that bind the active site of influenza neuraminidase. WO 92/06691. (CAN 117:131501)

    Google Scholar 

  27. Hagiwara T, Kijima-Suda I, Ido T, Ohrui H, Tomita K (1994) Inhibition of bacterial and viral sialidases by 3-fluoro-N-acetylneuraminic acid. Carbohydr Res 263:167–172

    Article  PubMed  CAS  Google Scholar 

  28. Watts AG, Damager I, Amaya ML, Buschiazzo A, Alzari P, Frasch AC, Withers SG (2003) Trypanosoma cruzi trans-sialidase operates through a covalent sialyl-enzyme intermediate: tyrosine is the catalytic nucleophile. J Am Chem Soc 125:7532–7533

    Article  PubMed  CAS  Google Scholar 

  29. Watts AG, Withers SG (2004) The synthesis of some mechanistic probes for sialic acid processing enzymes and the labeling of a sialidase from Trypanosoma rangeli. Can J Chem 82:1581–1588

    Article  CAS  Google Scholar 

  30. Taylor NR, von Itzstein M (1994) Molecular modeling studies on ligand binding to sialidase from influenza virus and the mechanism of catalysis. J Med Chem 37:616–624

    Article  PubMed  CAS  Google Scholar 

  31. Chan T-H, Xin Y-C, von Itzstein M (1997) Synthesis of phosphonic acid analogs of sialic acids (Neu5Ac and KDN) as potential sialidase inhibitors. J Org Chem 62:3500–3504

    Article  CAS  Google Scholar 

  32. White CL, Janakiraman MN, Laver WG, Philippon C, Vasella A, Air GM, Luo M (1995) A sialic acid-derived phosphonate analog inhibits different strains of influenza virus neuraminidase with different efficiencies. J Mol Biol 245:623–634

    Article  PubMed  CAS  Google Scholar 

  33. Yamamoto T, Kumazawa H, Inami K, Teshima T, Shiba T (1992) Syntheses of sialic acid isomers with inhibitory activity against neuraminidase. Tetrahedron Lett 33:5791–5794

    Article  CAS  Google Scholar 

  34. Babu YS, Chand P, Bantia S, Kotian P, Dehghani A, El-Kattan Y, Lin TH, Hutchison TL, Elliott AJ, Parker CD et al (2000) BCX-1812 (RWJ-270201): Discovery of a novel, highly potent, orally active, and selective influenza neuraminidase inhibitor through structure-based drug design. J Med Chem 43:3482–3486

    Article  PubMed  CAS  Google Scholar 

  35. Streicher H, Stanley M (2011) The development of non-carbohydrate-based influenza virus sialidase inhibitors. In: von Itzstein M (ed) Influenza virus sialidase: a drug discovery target. Springer, Heidelberg

    Google Scholar 

  36. Meindl P, Tuppy H (1969) Verfahren zur Herstellung neuer 2-Desoxy-2,3-dehydro-N-acyl-neuraminsäuren. DE 1493249. (CAN 78:30153)

    Google Scholar 

  37. Haverkamp J, Schauer R, Wember M, Farriaux J-P, Kamerling JP, Versluis C, Vliegenthart FG (1976) Neuraminic acid derivatives newly discovered in humans. Hoppe-Seyler’s Z Physiol Chem 357:1699–1705

    Article  PubMed  CAS  Google Scholar 

  38. Holzer CT, von Itzstein M, Jin B, Pegg MS, Stewart WP, Wu WY (1993) Inhibition of sialidases from viral, bacterial and mammalian sources by analogues of 2-deoxy-2, 3-didehydro-N-acetylneuraminic acid modified at the C-4 position. Glycoconjugate J 10:40–44

    Article  CAS  Google Scholar 

  39. Miller CA, Wang P, Flashner M (1978) Mechanism of Arthrobacter sialophilus neuraminidase: the binding of substrates and transition-state analogs. Biochem Biophys Res Commun 83:1479–1487

    Article  PubMed  CAS  Google Scholar 

  40. Furuhata K, Sato S, Goto M, Takayanagi H, Ogura H (1988) Studies on sialic acids. VII. The crystal and molecular structure of N-acetyl-2,3-dehydro-2-deoxyneuraminic acid. Chem Pharm Bull 36:1872–1876

    CAS  Google Scholar 

  41. Zbiral E, Brandstetter HH, Christian R, Schauer R (1987) Structural variations of N-acetylneuraminic acid. 7. Synthesis of the C-7-, C-8- and C-7, -8-side chain epimers of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid and their behavior towards sialidase from Vibrio cholerae. Liebigs Ann Chem: 781–786

    Google Scholar 

  42. Zbiral E, Schreiner E, Christian R, Kleineidam RG, Schauer R (1989) Structural variations of N-acetylneuraminic acid. 10. Synthesis of 2,7-, 2,8-, and 2,9-dideoxy- and 2,4,7-trideoxy-2, 3-didehydro-N-acetylneuraminic acids and their behavior towards sialidase from Vibrio cholerae. Liebigs Ann Chem: 159–165

    Google Scholar 

  43. Schreiner E, Zbiral E, Kleineidam RG, Schauer R (1991) Structural variations on N-acetylneuraminic acid, 20. Synthesis of some 2,3-didehydro-2-deoxysialic acids structurally varied at C-4 and their behavior towards sialidase from Vibrio cholerae. Liebigs Ann Chem: 129–134

    Google Scholar 

  44. Schreiner E, Zbiral E, Kleineidam RG, Schauer R (1991) Structural variations on N-acetylneuraminic acid. Part 21. 2,3-Didehydro-2-deoxysialic acids structurally varied at C-5 and their behavior toward the sialidase from Vibrio cholerae. Carbohydr Res 216:61–66

    Article  PubMed  CAS  Google Scholar 

  45. Vasella A, Wyler R (1991) Synthesis of a phosphonic acid analog of N-acetyl-2,3-didehydro-2-deoxyneuraminic acid, an inhibitor of Vibrio cholerae sialidase. Helv Chim Acta 74:451–463

    Article  CAS  Google Scholar 

  46. Zbiral E (1992) Synthesis of sialic acid analogues and their behaviour towards the enzymes of sialic acid metabolism and hemagglutinin X-31 of influenza A-virus. In: Ogura H, Hasegawa A, Suami T (eds) Carbohydrates. Synthetic methods and applications in medicinal chemistry. VCH, Weinheim, pp 304–339

    Google Scholar 

  47. Palese P, Schulman JL, Bodo G, Meindl P (1974) Inhibition of influenza and parainfluenza virus replication in tissue culture by 2-deoxy-2,3-dehydro-N-trifluoroacetylneuraminic acid (FANA). Virology 59:490–498

    Article  PubMed  CAS  Google Scholar 

  48. Palese P, Compans RW (1976) Inhibition of influenza virus replication in tissue culture by 2-deoxy-2,3-dehydro-N-trifluoroacetylneuraminic acid (FANA): mechanism of action. J Gen Virol 33:159–163

    Article  PubMed  CAS  Google Scholar 

  49. Palese P, Schulman JL (1977) Inhibitors of viral neuraminidase as potential antiviral drugs. In: Oxford JS (ed) Chemoprophylaxis and viral infection of the upper respiratory tract. CRC Press, Cleveland, Ohio, pp 189–202

    Google Scholar 

  50. Nöhle U, Beau JM, Schauer R (1982) Uptake, metabolism and excretion of orally and intravenously administered, double-labeled N-glycoloylneuraminic acid and single-labeled 2-deoxy-2,3-dehydro-N-acetylneuraminic acid in mouse and rat. Eur J Biochem 126:543–548

    Article  PubMed  Google Scholar 

  51. Varghese JN, Laver WG, Colman PM (1983) Structure of the influenza virus glycoprotein antigen neuraminidase at 2.9Å resolution. Nature 303:35–40

    Article  PubMed  CAS  Google Scholar 

  52. Varghese JN, Colman PM (1991) Three-dimensional structure of the neuraminidase of influenza virus A/Tokyo/3/67 at 2.2Å resolution. J Mol Biol 221:473–486

    Article  PubMed  CAS  Google Scholar 

  53. Goodford PJ (1985) A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. J Med Chem 28:849–857

    Article  PubMed  CAS  Google Scholar 

  54. Driguez PA, Barrere B, Quash G, Doutheau A (1994) Synthesis of transition-state analogs as potential inhibitors of sialidase from influenza-virus. Carbohydr Res 262:297–310

    Article  PubMed  CAS  Google Scholar 

  55. von Itzstein M, Wu W-Y, Jin B (1994) The synthesis of 2,3-didehydro-2,4-dideoxy-4-guanidinyl-N-acetylneuraminic acid: a potent influenza virus sialidase inhibitor. Carbohydr Res 259:301–305

    Article  Google Scholar 

  56. Hata K, Koseki K, Yamaguchi K, Moriya S, Suzuki Y, Yingsakmongkon S, Hirai G, Sodeoka M, von Itzstein M, Miyagi T (2008) Limited inhibitory effects of oseltamivir and zanamivir on human sialidases. Antimicrob Agents Chemother 52:3484–3491

    Article  PubMed  CAS  Google Scholar 

  57. Chavas LMG, Kato R, Suzuki N, von Itzstein M, Mann MC, Thomson RJ, Dyason JC, McKimm-Breschkin J, Fusi P, Tringali C et al (2010) Complexity in influenza virus targeted drug design: interaction with human sialidases. J Med Chem 53:2998–3002

    Article  PubMed  CAS  Google Scholar 

  58. Hart GJ, Bethell RC (1995) 2,3-Didehydro-2,4-dideoxy-4-guanidino-N-acetyl-D-neuraminic acid (4-guanidino-Neu5Ac2en) is a slow-binding inhibitor of sialidase from both influenza A virus and influenza B virus. Biochem Mol Biol Int 36:695–703

    PubMed  CAS  Google Scholar 

  59. Bantia S, Parker CD, Ananth SL, Horn LL, Andries K, Chand P, Kotian PL, Dehghani A, El Kattan Y, Lin T et al (2001) Comparison of the anti-influenza virus activity of RWJ-270201 with those of oseltamivir and zanamivir. Antimicrob Agents Chemother 45:1162–1167

    Article  PubMed  CAS  Google Scholar 

  60. Kati WM, Montgomery D, Carrick R, Gubareva L, Maring C, McDaniel K, Steffy K, Molla A, Hayden F, Kempf D et al (2002) In vitro characterization of A-315675, a highly potent inhibitor of A and B strain influenza virus neuraminidases and influenza virus replication. Antimicrob Agents Chemother 46:1014–1021

    Article  PubMed  CAS  Google Scholar 

  61. Govorkova EA, Leneva IA, Goloubeva OG, Bush K, Webster RG (2001) Comparison of efficacies of RWJ-270201, zanamivir, and oseltamivir against H5N1, H9N2, and other avian influenza viruses. Antimicrob Agents Chemother 45:2723–2732

    Article  PubMed  CAS  Google Scholar 

  62. Waghorn SL, Goa KL (1998) Zanamivir. Drugs 55:721–725

    Article  PubMed  CAS  Google Scholar 

  63. Elliott M (2001) Zanamivir: from drug design to the clinic. Phil Trans R Soc Lond B Biol Sci 356:1885–1893

    Article  CAS  Google Scholar 

  64. von Itzstein M (2007) The war against influenza: discovery and development of sialidase inhibitors. Nat Rev Drug Discov 6:967–974

    Article  CAS  Google Scholar 

  65. von Itzstein M, Thomson R (2009) Anti-influenza drugs: the development of sialidase inhibitors. Handb Exp Pharmacol 189:111–154

    Article  Google Scholar 

  66. Woods JM, Bethell RC, Coates JAV, Healy N, Hiscox SA, Pearson BA, Ryan DM, Ticehurst J, Tilling J, Walcott SM et al (1993) 4-Guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid is a highly effective inhibitor both of the sialidase (neuraminidase) and of growth of a wide range of influenza-A and influenza-B viruses in vitro. Antimicrob Agents Chemother 37:1473–1479

    PubMed  CAS  Google Scholar 

  67. Varghese JN, Epa VC, Colman PM (1995) Three-dimensional structure of the complex of 4-guanidino-Neu5Ac2en and influenza virus neuraminidase. Protein Sci 4:1081–1087

    Article  PubMed  CAS  Google Scholar 

  68. Morris SJ, Price GE, Barnett JM, Hiscox SA, Smith H, Sweet C (1999) Role of neuraminidase in influenza virus-induced apoptosis. J Gen Virol 80:137–146

    PubMed  CAS  Google Scholar 

  69. Monti E, Preti A, Venerando B, Borsani G (2002) Recent development in mammalian sialidase molecular biology. Neurochem Res 27:649–663

    Article  PubMed  CAS  Google Scholar 

  70. Calfee DP, Peng AW, Cass LM, Lobo M, Hayden FG (1999) Safety and efficacy of intravenous zanamivir in preventing experimental human influenza A virus infection. Antimicrob Agents Chemother 43:1616–1620

    PubMed  CAS  Google Scholar 

  71. Kidd IM, Down J, Nastouli E, Shulman R, Grant PR, Howell DC, Singer M (2009) H1N1 pneumonitis treated with intravenous zanamivir. Lancet 374:1036

    Article  PubMed  Google Scholar 

  72. Gaur AH, Bagga B, Barman S, Hayden R, Lamptey A, Hoffman JM, Bhojwani D, Flynn PM, Tuomanen E, Webby R (2010) Intravenous zanamivir for oseltamivir-resistant 2009 H1N1 influenza. N Engl J Med 362:88–89

    Article  PubMed  CAS  Google Scholar 

  73. Buchy P (2011) Clinical experience with influenza virus sialidase inhibitors. In: von Itzstein M (ed) Influenza virus sialidase: a drug discovery target. Springer, Heidelberg

    Google Scholar 

  74. Ryan DM, Ticehurst J, Dempsey M, Penn CR (1994) Inhibition of influenza virus replication in mice by GG167 (4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid) is consistent with extracellular actiivity of viral neuraminidase (sialidase). Antimicrob Agents Chemother 10:2270–2275

    Google Scholar 

  75. Liu Z-Y, Wang B, Zhao L-X, Li Y-H, Shao H-Y, Yi H, You X-F, Li Z-R (2007) Synthesis and anti-influenza activities of carboxyl alkoxyalkyl esters of 4-guanidino-Neu5Ac2en (zanamivir). Bioorg Med Chem Lett 17:4851–4854

    Article  PubMed  CAS  Google Scholar 

  76. Honda T, Masuda T, Yoshida S, Arai M, Kobayashi Y, Yamashita M (2002) Synthesis and anti-influenza virus activity of 4-guanidino-7-substituted Neu5Ac2en derivatives. Bioorg Med Chem Lett 12:1921–1924

    Article  PubMed  CAS  Google Scholar 

  77. Yamashita M (2004) R-118958, a unique anti-influenza agent showing high efficacy for both prophylaxis and treatment after a single administration: from the in vitro stage to phase I study. Int Congress Ser 1263:38–42

    Article  CAS  Google Scholar 

  78. Yamashita M, Tomozawa T, Kakuta M, Tokumitsu A, Nasu H, Kubo S (2009) CS-8958, a prodrug of the new neuraminidase inhibitor R-125489, shows long-acting anti-influenza virus activity. Antimicrob Agents Chemother 53:186–192

    Article  PubMed  CAS  Google Scholar 

  79. Honda T, Kubo S, Masuda T, Arai M, Kobayashi Y, Yamashita M (2009) Synthesis and in vivo influenza virus-inhibitory effect of ester prodrug of 4-guanidino-7-O-methyl-Neu5Ac2en. Bioorg Med Chem Lett 19:2938–2940

    Article  PubMed  CAS  Google Scholar 

  80. Koyama K, Takahashi M, Oitate M, Nakai N, Takakusa H, S-i M, Okazaki O (2009) CS-8958, a prodrug of the novel neuraminidase inhibitor R-125489, demonstrates a favorable long-retention profile in the mouse respiratory tract. Antimicrob Agents Chemother 53:4845–4851

    Article  PubMed  CAS  Google Scholar 

  81. Kubo S, Tomozawa T, Kakuta M, Tokumitsu A, Yamashita M (2010) Laninamivir prodrug CS-8958, a long-acting neuraminidase inhibitor, shows superior anti-influenza virus activity after a single administration. Antimicrob Agents Chemother 54:1256–1264

    Article  PubMed  CAS  Google Scholar 

  82. Kiso M, Kubo S, Ozawa M, Le QM, Nidom CA, Yamashita M, Kawaoka Y (2010) Efficacy of the new neuraminidase inhibitor CS-8958 against H5N1 influenza viruses. PLoS Pathog 6:e1000786

    Article  PubMed  CAS  Google Scholar 

  83. Honda T, Masuda T, Yoshida S, Arai M, Kaneko S, Yamashita M (2002) Synthesis and anti-Influenza virus activity of 7-O-alkylated derivatives related to zanamivir. Bioorg Med Chem Lett 12:1925–1928

    Article  PubMed  CAS  Google Scholar 

  84. Andrews DM, Cherry PC, Humber DC, Jones PS, Keeling SP, Martin PF, Shaw CD, Swanson S (1999) Synthesis and influenza virus sialidase inhibitory activity of analogues of 4-guanidino-Neu5Ac2en (Zanamivir) modified in the glycerol side-chain. Eur J Med Chem 34:563–574

    PubMed  CAS  Google Scholar 

  85. Watson KG, Cameron R, Fenton RJ, Gower D, Hamilton S, Jin B, Krippner GY, Luttick A, McConnell D, MacDonald SJ et al (2004) Highly potent and long-acting trimeric and tetrameric inhibitors of influenza virus neuraminidase. Bioorg Med Chem Lett 14:1589–1592

    Article  PubMed  CAS  Google Scholar 

  86. Honda T, Yoshida S, Arai M, Masuda T, Yamashita M (2002) Synthesis and anti-influenza evaluation of polyvalent sialidase inhibitors bearing 4-guanidino-Neu5Ac2en derivatives. Bioorg Med Chem Lett 12:1929–1932

    Article  PubMed  CAS  Google Scholar 

  87. Macdonald SJ, Watson KG, Cameron R, Chalmers DK, Demaine DA, Fenton RJ, Gower D, Hamblin JN, Hamilton S, Hart GJ et al (2004) Potent and long-acting dimeric inhibitors of influenza virus neuraminidase are effective at a once-weekly dosing regimen. Antimicrob Agents Chemother 48:4542–4549

    Article  PubMed  CAS  Google Scholar 

  88. Macdonald SJ, Cameron R, Demaine DA, Fenton RJ, Foster G, Gower D, Hamblin JN, Hamilton S, Hart GJ, Hill AP et al (2005) Dimeric zanamivir conjugates with various linking groups are potent, long-lasting inhibitors of influenza neuraminidase including H5N1 avian influenza. J Med Chem 48:2964–2971

    Article  PubMed  CAS  Google Scholar 

  89. Wen W-H, Lin M, Su C-Y, Wang S-Y, Cheng Y-SE, Fang J-M, Wong C-H (2009) Synergistic effect of zanamivir–porphyrin conjugates on inhibition of neuraminidase and inactivation of influenza virus. J Med Chem 52:4903–4910

    Article  PubMed  CAS  Google Scholar 

  90. Sun X-L (2007) Recent anti-influenza strategies in multivalent sialyloligosaccharides and sialylmimetics approaches. Curr Med Chem 14:2304–2313

    Article  PubMed  CAS  Google Scholar 

  91. Haldar J, Alvarez de Cienfuegos L, Tumpey TM, Gubareva LV, Chen J, Klibanov AM (2010) Bifunctional polymeric inhibitors of human influenza A viruses. Pharm Res 27:259–263

    Article  PubMed  CAS  Google Scholar 

  92. Bamford MJ (1995) Neuraminidase inhibitors as potential anti-influenza drugs. J Enzyme Inhib 10:1–16

    Article  CAS  Google Scholar 

  93. Thomson RJ, von Itzstein M (2003) N-Acetylneuraminic acid derivatives and mimetics as anti-influenza agents. In: Wong C-H (ed) Carbohydrate-based drug discovery. Wiley-VCH, Weinheim, pp 831–862

    Google Scholar 

  94. Streicher H (2004) Synthesis and evaluation as sialidase inhibitors of xylo-configured cyclohexene-phosphonates carrying glycerol side-chain mimics. Bioorg Med Chem Lett 14:361–364

    Article  PubMed  CAS  Google Scholar 

  95. Shie J-J, Fang J-M, Wang S-Y, Tsai K-C, Cheng Y-SE, Yang A-S, Hsiao S-C, Su C-Y, Wong C-H (2007) Synthesis of Tamiflu and its phosphonate congeners possessing potent anti-influenza activity. J Am Chem Soc 129:11892–11893

    Article  PubMed  CAS  Google Scholar 

  96. Carbain B, Collins PJ, Callum L, Martin SR, Hay AJ, McCauley J, Streicher H (2009) Efficient synthesis of highly active phospha-isosteres of the influenza neuraminidase inhibitor oseltamivir. ChemMedChem 4:335–337

    Article  PubMed  CAS  Google Scholar 

  97. Chandler M, Bamford MJ, Conroy R, Lamont B, Patel B, Patel VK, Steeples IP, Storer R, Weir NG, Wright M et al (1995) Synthesis of the potent influenza neuraminidase inhibitor 4-guanidino-Neu5Ac2en. X-Ray molecular structure of 5-acetamido-4-amino-2,6-anhydro-3,4,5-trideoxy-D-erythro-L-gluco-nononic acid. J Chem Soc Perkin Trans 1:1173–1180

    Article  Google Scholar 

  98. Ikeda K, Sano K, Ito M, Saito M, Hidari K, Suzuki T, Suzuki Y, Tanaka K (2001) Synthesis of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid analogues modified at the C-4 and C-9 positions and their behavior towards sialidase from influenza virus and pig liver membrane. Carbohydr Res 330:31–41

    Article  PubMed  CAS  Google Scholar 

  99. Wen W-H, Wang S-Y, Tsai K-C, Cheng Y-SE, Yang A-S, Fang J-M, Wong C-H (2010) Analogs of zanamivir with modified C4-substituents as the inhibitors against the group-1 neuraminidases of influenza viruses. Bioorg Med Chem 18:4074–4084

    Article  PubMed  CAS  Google Scholar 

  100. Li J, Zheng M, Tang W, He P-L, Zhu W, Li T, Zuo J-P, Liu H, Jiang H (2006) Syntheses of triazole-modified zanamivir analogs via click chemistry and anti-AIV activities. Bioorg Med Chem Lett 16:5009–5013

    Article  PubMed  CAS  Google Scholar 

  101. Bamford MJ, Pichel JC, Husman W, Patel B, Storer R, Wier NG (1995) Synthesis of 6-, 7- and 8-carbon sugar analogs of potent anti-influenza 2,3-didehydro-2,3-dideoxy-N-acetylneuraminic acid derivatives. J Chem Soc Perkin Trans 1:1181–1187

    Article  Google Scholar 

  102. Masuda T, Shibuya S, Arai M, Yoshida S, Tomozawa T, Ohno A, Yamashita M, Honda T (2003) Synthesis and anti-influenza evaluation of orally active bicyclic ether derivatives related to zanamivir. Bioorg Med Chem Lett 13:669–673

    Article  PubMed  CAS  Google Scholar 

  103. Smith PW, Sollis SL, Howes PD, Cherry PC, Cobley KN, Taylor H, Whittington AR, Scicinski J, Bethell RC, Taylor N et al (1996) Novel inhibitors of influenza sialidases related to GG167. Structure-actvity, crystallographic and molecular dynamics studies with 4-H-pyran-2-carboxylic acid 6-carboxamides. Bioorg Med Chem Lett 6:2931–2936

    Article  CAS  Google Scholar 

  104. Smith PW, Sollis SL, Howes PD, Cherry PC, Starkey ID, Cobley KN, Weston H, Scicinski J, Merritt A, Whittington A et al (1998) Dihydropyrancarboxamides related to zanamivir: a new series of inhibitors of influenza virus sialidases. 1. Discovery, synthesis, biological activity, and structure-activity relationships of 4-guanidino- and 4-amino-4 H-pyran-6-carboxamides. J Med Chem 41:787–797

    Article  PubMed  CAS  Google Scholar 

  105. Wyatt PG, Coomber BA, Evans DN, Jack TI, Fulton HE, Wonacott AJ, Colman P, Varghese J (2001) Sialidase inhibitors related to zanamivir. Further SAR studies of 4-amino-4 H-pyran-2-carboxylic acid-6-propylamides. Bioorg Med Chem Lett 11:669–673

    Article  PubMed  CAS  Google Scholar 

  106. Taylor NR, Cleasby A, Singh O, Skarzynski T, Wonacott AJ, Smith PW, Sollis SL, Howes PD, Cherry PC, Bethell R et al (1998) Dihydropyrancarboxamides related to zanamivir: a new series of inhibitors of influenza virus sialidases. 2. Crystallographic and molecular modeling study of complexes of 4-amino-4 H-pyran-6-carboxamides and sialidase from influenza virus types A and B. J Med Chem 41:798–807

    Article  PubMed  CAS  Google Scholar 

  107. Vorwerk S, Vasella A (1998) Carbocyclic analogs of N-acetyl-2,3-didehydro-2-deoxy D-neuraminic acid (Neu5Ac2en, DANA): synthesis and inhibition of viral and bacterial neuraminidases. Angew Chem Int Ed Engl 37:1732–1734

    Article  CAS  Google Scholar 

  108. Lew W, Chen X, Kim CU (2000) Discovery and development of GS 4104 (oseltamivir): an orally active influenza neuraminidase inhibitor. Curr Med Chem 7:663–672

    PubMed  CAS  Google Scholar 

  109. Kim CU, Lew W, Williams MA, Liu H, Zhang L, Swaminathan S, Bischofberger N, Chen MS, Mendel DB, Tai CY et al (1997) Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. J Am Chem Soc 119:681–690

    Article  PubMed  CAS  Google Scholar 

  110. Smith PW, Robinson JE, Evans DN, Sollis SL, Howes PD, Trivedi N, Bethell RC (1999) Sialidase inhibitors related to zanamivir: synthesis and biological evaluation of 4 H-pyran 6-ether and ketone. Bioorg Med Chem Lett 9:601–604

    Article  PubMed  CAS  Google Scholar 

  111. Florio P, Thomson RJ, Alafaci A, Abo S, von Itzstein M (1999) Synthesis of Δ-4-β- D-glucopyranosiduronic acids as mimetics of 2,3-unsaturated sialic acids for sialidase inhibition. Bioorg Med Chem Lett 9:2065–2068

    Article  PubMed  CAS  Google Scholar 

  112. Mann MC, Islam T, Dyason JC, Florio P, Trower CJ, Thomson RJ, von Itzstein M (2006) Unsaturated N-acetyl-D-glucosaminuronic acid glycosides as inhibitors of influenza virus sialidase. Glycoconjugate J 23:127–133

    Article  CAS  Google Scholar 

  113. Mann MC, Thomson RJ, Dyason JC, McAtamney S, von Itzstein M (2006) Modelling, synthesis and biological evaluation of novel glucuronide-based probes of Vibrio cholerae sialidase. Bioorg Med Chem 14:1518–1537

    Article  PubMed  CAS  Google Scholar 

  114. Kok GB, Campbell M, Mickey B, von Itzstein M (1996) Synthesis and biological evaluation of sulfur isosteres of the potent influenza virus sialidase inhibitors 4-amino-4-deoxy- and 4-deoxy-4-guanidino-Neu5Ac2en. J Chem Soc Perkin Trans 1:2811–2815

    Article  Google Scholar 

  115. Kerrigan SA, Pritchard RG, Smith PW, Stoodley RJ (2001) Synthesis of (4R*,5 S*)- 5-(acetylamino)-4-(diethylcarbamoyl)-5,6-dihydro-4 H-pyran-2-carboxylic acid and its inhibitory action against influenza virus sialidases. Tetrahedron Lett 42:8889–8892

    Article  CAS  Google Scholar 

  116. Meanwell NA, Krystal M (1996) Taking aim at a moving target - Inhibitors of influenza virus.1. Virus adsorption, entry and uncoating. Drug Discov Today 1:316–324

    Article  CAS  Google Scholar 

  117. Meanwell NA, Krystal M (1996) Taking aim at a moving target - Inhibitors of influenza virus. 2. Viral replication, packaging and release. Drug Discov Today 1:388–397

    Article  CAS  Google Scholar 

  118. Lagoja IM, De Clercq E (2008) Anti-influenza agents: synthesis and mode of action. Med Res Rev 28:1–38

    Article  PubMed  CAS  Google Scholar 

  119. Hayden F (2009) Developing new antiviral agents for influenza treatment: what does the future hold? Clin Infect Dis 48:S3–S13

    Article  PubMed  CAS  Google Scholar 

  120. Furuta Y, Takahashi K, Shiraki K, Sakamoto K, Smee DF, Barnard DL, Gowen BB, Julander JG, Morrey JD (2009) T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections. Antiviral Res 82:95–102

    Article  PubMed  CAS  Google Scholar 

  121. Triana-Baltzer GB, Babizki M, Chan MCW, Wong ACN, Aschenbrenner LM, Campbell ER, Li Q-X, Chan RWY, Peiris JS, Nicholls JM et al (2010) DAS181, a sialidase fusion protein, protects human airway epithelium against influenza virus infection: an in vitro pharmacodynamic analysis. J Antimicrob Chemother 65:275–284

    Article  PubMed  CAS  Google Scholar 

  122. Triana-Baltzer GB, Gubareva LV, Nicholls JM, Pearce MB, Mishin VP, Belser JA, Chen L-M, Chan RWY, Chan MCW, Hedlund M et al (2009) Novel pandemic influenza A(H1N1) viruses are potently inhibited by DAS181, a sialidase fusion protein. PLoS One 4:e7788

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The financial support of the Australian Research Council (ARC) through the award of an Australian Federation Fellowship (MvI), the National Health and Medical Research Council (NHMRC), and the Honda Foundation (Australia) is gratefully acknowledged.

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  1. Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, QLD, 4222, Australia

    Robin Thomson & Mark von Itzstein

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Correspondence to Robin Thomson .

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    Mark von Itzstein

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Thomson, R., von Itzstein, M. (2012). The Development of Carbohydrate-Based Influenza Virus Sialidase Inhibitors. In: von Itzstein, M. (eds) Influenza Virus Sialidase - A Drug Discovery Target. Milestones in Drug Therapy. Springer, Basel. https://doi.org/10.1007/978-3-7643-8927-7_5

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